This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Judith LaLonde, Bryn Mawr College: Development of Novel HIV Entry Inhibitors Using the ROCS Shaped Based Matching Algorithm The key objective of this computational project is to rationally design small-molecule antagonists that block the interaction between the human CD4 cell-surface receptor and the gp120 envelop protein of HIV-1 as potential therapeutics for the treatment of AIDS. The viral envelop protein, gp120, undergoes a large conformational change upon binding to the cellular CD4 receptor allowing subsequent binding to the chemokine receptor and viral-host cell fusion (1). The NIH PO1 GM 56550 project team (Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry) has synthesized and assayed a series of NBD compound analogs (2) (Figure 1). These compounds compete with CD4 binding to gp120 and enhance binding of CD4:gp120 to the chemokine receptor CCR5. Elucidation of the thermodynamic properties of NBD compounds via isothermal titration calorimetry by Schon et al (2) indicates that this compound class induces the structuring of gp120 in a manner similar to CD4 binding. These compounds enhance and inactive the virus prior to binding to the cellular receptor. A predicted binding mode for this class of compounds has been produced from computational docking studies using Glide (3, 4), (Figure 1). Mutational analysis of the series of NBD compounds with key binding site residues has shown certain compounds and mutations increase binding affinity and enhance viral infectivity (7). This mutational data provides information of key protein interactions responsible for the agonistic properties of the compounds. Over the course of the current allocation the conformer data base of the Zinc collection (8) of 8 million drug-like compounds was used with ROCS (9-11) shaped-based virtual screening methods. This screening protocol was used to identify, synthesize and test over 100 new small molecule analogues of HIV gp120-CD4 binding (12). Over twenty of these are promising new analogues for further optimization. The ROCS screening protocol will continue to be used in the optimization process under the requested renewal period (4-1-11 to 3-31-12). A resource of 90,000 SU on Warhol at the Pittsburgh Super Computing Center as well as Advanced Technical Support for software and PVM support when updates are available is requested. Continued, rapid, virtual screening using PSC resources will further promote the discovery of HIV entry inhibitors.